Methods of synthesis and use of radiolabelled platinum chemotherapeutic agents

ABSTRACT

There is provided a method of synthesis of a radiolabelled platinum chemotherapeutic agent comprising the steps of: converting a metal halide to a radiolabelled platinum halide wherein the radiolabel is a radioisotope of Pt; and synthesising the radiolabelled platinum chemotherapeutic agent from the radiolabelled platinum halide.

BRIEF SUMMARY OF THE INVENTION

[0001] The present invention relates to methods of synthesis ofradiolabelled platinum chemotherapeutic agents including radiolabelledcis-platin. The present invention also relates to methods of diagnosisof diseases, methods of therapy of diseases, methods of prognosis ofdiseases, and methods of assessing the effectiveness of treatment ofdiseases using radiolabelled platinum chemotherapeutic agents.

BACKGROUND OF THE INVENTION

[0002] The treatment of cancer typically requires the optimal sequenceof one or more of the effective treatments (e.g. surgery, radiotherapy,and chemotherapy). Patients for whom the disease is at an early stagecan frequently be operated on to remove the cancer. In many cancersfollow up adjuvant chemotherapy is required for micro-metastaticdisease. In others with locally advanced or metastatic disease, cancercontrol relies on radiotherapy it and/or chemotherapy. In cancertherapy, failure to cure the disease generally results from intrinsic oracquired tumour cell resistance to drugs or radiotherapy. In suchinstances, the treatments become ineffective and survival times for suchpatients may be considerably reduced. Thus it is important to developnew approaches to cancer which may enhance the cytotoxicity of knownchemotherapeutic agents.

[0003] The combination of external radiation and chemotherapy has inmany instances been reported to have a synergistic effect on therapy.However, combining these two modalities effectively relies on anunending of the mechanisms that lead to the enhanced therapeutic indexand the exploitable differences in the properties of tumours and normaltissues.

[0004] Platinum based chemotherapeutic agents are used in the treatmentof cancers. These agents exert their cytotoxic effect by binding withthe DNA of the cancer cell and causing strand breaks, and consequentlypreventing the cell from dividing further and causing cell death. Anumber of mechanisms are manifested in in vitro resistance to thechemotherapeutic agents. They are usually manifested in decreasedtransport of the drug into the cell, thiol inactivation, enhanced DNArepair or a combination of some or all of these mechanisms. There is aneed for an effective method to monitor the development of resistance toplatinum based chemotherapeutic agents in vivo, and for an effectivemethod for assessing the effectiveness of treatment of diseases such ascancer which are undergoing treatment by administration of a platinumbased chemotherapeutic agent.

[0005] Cisplatin (cis-dichlorodiammine-platinum (II)) and carboplatin(cis-diammine(1,1-cyclobutanedicarboxylate) platinum (II)) are the twomost widely prescribed platinum based chemotherapeutic agents at thepresent time. Reports have appeared in the literature of the use ofradiolabelled cisplatin to assess the biodistribution of cisplatin inanimals. However, to date there has been no medical use of radiolabelledplatinum based therapeutic agents. The methods whereby radiolabelledcisplatin has hitherto been prepared suffer from a number ofdisadvantages. They use as their starting point platinum metal which hasbeen enriched in a radioisotope of platinum by irradiation of platinummetal in a nuclear reactor, typically with neutrons.

[0006] Starting with platinum metal, the synthesis of radiolabelledcisplatin is relatively time consuming requiring in the order of 6.5hours to complete. For radionuclides with half-lives of hours, a fewhours' delay in the preparation of radiolabelled cisplatin can lead tosignificant loss of specific activity, especially as in a productionenvironment this amount of delay may result in product only reaching apatient on the following working day. Such a delay causes significantloss of specific activity of the radioisotope. In this instance, inorder for a desired amount of radioactivity to be administered to apatient, the overall dosage of unradiolabelled cisplatin carrier will beincreased as the specific activity of the radiolabelled substancedecreases. It may then become impractical to administer sufficient ofthe agent to deliver the desired amount of radioactivity if the specificactivity is too low.

[0007] By contrast, a significantly shorter synthesis time can permitthe distribution of the product and its administration to the patient onthe same day as the agent is administered, without the concomitant lossin specific activity.

[0008] Furthermore the prior art synthesis of cisplatin from platinummetal exhibits relatively low and variable yields, and is unreliable andmay at times give no yield of the desired product. Low yield ofradiolabelled cisplatin or other radiolabelled chemotherapeutic agentsstarting with radiolabelled platinum metal (which is expensive) resultsin a high cost of the radiolabelled chemotherapeutic agent and thepossibility of insufficient dose being available for treatment of apatient. Similarly, unreliability of prior art synthetic methods and theoccurrence of failures is totally unsatisfactory in a clinical context.

[0009] Still further, the “hot cell” facilities required for diesynthesis of a radiolabelled chemotherapeutic such as cisplatin areexpensive and there are significant economic benefits to be gained froma shortened synthesis, permitting greater throughput in the hot cell.

[0010] There is therefore a need for a shortened and more reliablemethod of synthesis of radiolabelled platinum based chemotherapeuticagents.

[0011] The present invention seeks to provide methods of synthesis ofradiolabelled platinum based chemotherapeutic agents which provide adecrease in the synthesis time compared to previously known methods, andimproved, more reliable yields, thereby allowing greater scopediagnostic, therapeutic and related applications.

[0012] The present invention also seeks to provide methods ofincorporation of radionuclides such as ^(195m)Pt with both an imageableand a therapeutic emission into platinum based chemotherapeutic agentsto facilitate use of the resultant radiolabelled agent (a) to determinethe appropriate dosage of the chemotherapeutic agent in a patient,and/or (b) to determine the effectiveness of the chemotherapeutic agentin a patient, and/or (c) as a monitor of drug resistance and/or (d) toenhance cytotoxic effects by exploiting synergistic cytotoxicdrug-radiation interactions.

SUMMARY OF THE INVENTION

[0013] Throughout the specification, unless the context clearlyindicates otherwise, the words “comprise”, “comprises”, “comprising” orother variations thereof shall be understood as meaning that the statedinteger is included and does not exclude other integers from beingpresent even though those other integers are not explicitly stated.

[0014] In accordance with a first embodiment of the present invention,there is provided a method of synthesis of a radiolabelled platinumchemotherapeutic agent comprising the steps of:

[0015] a) converting a metal halide to a radiolabelled platinum halidewherein the radiolabel is a radioisotope of Pt; and

[0016] (b) synthesising the radiolabelled platinum chemotherapeuticagent from the radiolabelled platinum halide.

[0017] In accordance with a second embodiment of the present invention,there is provided a method of synthesis of cisplatin or carboplatincomprising the steps of:

[0018] a) converting a metal chloride to radiolabelled PtCl₂ wherein theradiolabel is a radioisotope of Pt; and

[0019] b) synthesising cisplatin or carboplatin from the radiolabelledPtCl₂.

[0020] In accordance with a third embodiment of the present invention,there is provided a radiolabelled platinum chemotherapeutic agentproduced by the method of synthesis of the first or second embodimentsof the present invention.

[0021] In accordance with a fourth embodiment of the present invention,there is provided a method of assessing the effectiveness of treatmentof a disease such as cancer wherein said treatment comprisesadministration of a platinum chemotherapeutic agent to a subject, whichmethod comprises the steps of administering to said subject saidplatinum chemotherapeutic agent which is a radiolabelled platinumchemotherapeutic agent of the third embodiment of the present invention,in an amount sufficient to permit uptake or clearance of said radiolabelto be monitored in said subject and monitoring said subject.

[0022] In accordance with a fifth embodiment of the present invention,there is provided a method of diagnosis of a disease such as cancer in asubject comprising the steps of administering an effective amount of aradiolabelled platinum chemotherapeutic agent of the third embodiment ofthe present invention to said subject and monitoring said subject.

[0023] In accordance with a sixth embodiment of the present invention,there is provided a method of therapy of a disease such as cancer in asubject comprising the steps of administering an effective amount of aradiolabelled platinum chemotherapeutic agent of the third embodiment ofthe present invention to said subject.

[0024] In accordance with a seventh embodiment of the present invention,there is provided a method of prognosis of a disease such as cancer in asubject comprising the steps of administering an effective amount of aradiolabelled platinum chemotherapeutic agent of the third embodiment ofthe present invention to said subject and monitoring said subject.

[0025] In accordance with an eighth embodiment of the present invention,there is provided a use of a radiolabelled platinum chemotherapeuticagent of the third embodiment of the present invention in thepreparation of a medicament for diagnosis, prognosis, therapy orassessment of the effectiveness of treatment of a disease such ascancer.

[0026] In accordance with a ninth embodiment of the present invention,there is provided a radiolabelled platinum chemotherapeutic agent of thethird embodiment of the present invention when used in diagnosis,prognosis, therapy or assessing the effectiveness of treatment of adisease such as cancer.

[0027] Whilst the methods of the fourth to seventh embodiments aretypically provided in relation to cancer, they are also applicable toother diseases which are able to be treated by platinum basedchemotherapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

[0028] Usually, in the method of synthesis of the radiolabelled platinumchemotherapeutic agent the step of converting the metal halide into aradiolabelled platinum halide is carried out in a nuclear reactor or acyclotron. Typically this conversion step is carried out by irradiationwith neutrons in a nuclear reactor. The radiolabelled platinum halidemay be a Pt(II) halide or a Pt(IV) halide. More typically, the presentinvention involves irradiating a Pt(II) halide, even more typicallyPtCl₂, with neutrons in a nuclear reactor. Alternatively, the metalhalide may be the halide of a metal such as gold, iridium, etc. whichcan be converted into platinum by bombardment with protons, deuterons,alpha particles or other species in a cyclotron. In a typicalembodiment, the radiolabelled platinum halide is a Pt(II) halide whichis converted to cisplatin or carboplatin.

[0029] The platinum radioisotope in the synthetic method of the first orsecond embodiments is typically selected from the group consisting of^(195m)Pt, ^(197m)Pt, ¹⁹⁷Pt, 197Pt, ^(193m)Pt and mixtures thereof.Still more typically, the radioisotope is ^(195m)Pt or ^(193m)Pt. Yetstill more typically, the radioisotope is ^(195m)Pt.

[0030] The radioisotopes of platinum may be prepared by methods whichare generally known in the art. For example, radioactive halides ofplatinum which incorporate ^(193m)Pt, ^(195m)Pt or ¹⁹⁷Pt may be preparedby irradiating a halide of ¹⁹²Pt, ¹⁹⁴Pt and ¹⁹⁶Pt, respectively (inoxidation state II or IV) with neutrons in a nuclear reactor. It willappreciated that the irradiation time to achieve a predeterminedspecific activity will be dependent on the nuclear reactor flux. Thoseversed in the art will readily determine the appropriate irradiationtime for a given facility's flux.

[0031] It will be appreciated that when the platinum chemotherapeuticagent is a Pt(IV) species, the method of the present invention willusually include the steps of converting a metal halide to aradiolabelled Pt(IV) halide and synthesising the radiolabelled platinumchemotherapeutic agent from the radio label led Pt(TV) halide.

[0032] Typically, the platinum chemotherapeutic agents are selected fromplatinum coordination compounds which show cytotoxic properties andstill more typically are platinum coordination compounds which showactivity against cancer cells. The substituents on the platinumcoordination compounds way be selected from the group consisting of NH₃,cyclic amino, alkylamino, arylamino, cycloalkylamino, aralkylamino, halo(especially chloro), hydroxy, alkoxy, carbarnate, carbonate ester,carboxylate, sulfate, sulfonate, phosphate, phosphonate, nitrate andbi-dentate ligands such as dicarboxylate, sulphate, phosphate ornitrate.

[0033] These platinum coordination compounds may be selected fromplatinum (II) and platinum (IV) coordination compounds and comprisethose platinum (II) and platinum (I) compounds with substituents in boththe cis and trans configurations.

[0034] Still more typically, the platinum compounds are of the followinggeneral formulae (I) and (II);

[0035] where each A is independently selected from halo (especiallychloro), hydroxy, alkoxy and carboxylate or in which two A ligandstogether form a bi-dentate ligand such as di-carboxylate, sulphate,nitrate or phosphate;

[0036] each B, which may be the same or different, is selected fromhalo, hydroxy, carboxylate, carbarnate and carbonate ester:

[0037] Z and X are independently NH₃, cyclic amine, alkylamino,arylamino, cycloalkylamino, and aralkylamino,

[0038] or Z and X together are H₂N-Q-NH₂ wherein Q is a divalent moietyselected from alkylene, cycloalkyl, aryl and aralkyl.

[0039] Typically the complex is of formula I.

[0040] In one embodiment, Z is a cyclic amine, where the ring maycontain one or more other heteroatoms, which may be farther substituted,typically by substituents on the atom adjacent to the amine nitrogenatom. The cyclic amine may be a 5- or 6-membered monocyclic or 8 to10-membered polycyclic, especially bicyclic, amine for example includinga fused ring system where the amine is coordinated through the nitrogenatom of a pyridine ring. In the case of such bicyclic fused ringsystems, the other ring may be phenylene or may contain one or moreheteroatoms, especially nitrogen or oxygen. Typically the cyclic amineis an unsaturated amine, more typically pyridine.

[0041] In the case of substituted cyclic amines, the substituent may bealkyl of 1 to 6 carbon atoms or alkoxy of 1 to 4 carbon atoms(especially methyl or methoxy), nitro, halo (especially chloro orbromo), aryl or aralkyl (especially benzyl). The substituent may itselfbe substituted by halogen. The cyclic amine may carry other substituentseither adjacent to the coordinating nitrogen atom or elsewhere on thering.

[0042] Typically, in formula (I) or (II) each A is the same, and is moretypically chloro, or together two A ligands, when present, formcyclobutane-1,1-dicarboxylate or sulphate. In the case of Pt(IV)complexes of formula II, typically each B is the same, and moretypically is hydroxy.

[0043] More typically, the platinum coordination compounds are selectedfrom cisplatin, carboplatin and other platinum malonato coordinationcompounds. The term “malonato compounds” is understood to mean thoseplatinum coordination compounds that comprise in their structure a(—OOC)₂—C<linkage. Still more typically, die chemotherapeutic agent iscarboplatin or cisplatin, and yet more typically cisplatin.

[0044] Examples of platinum chemotherapeutic agents are described inU.S. Pat. Nos. 3,904,663, 4,115,418, 4,137,248, 4,140,707, 4,169,846,4,203,912, 4,225,529, 4,230,631, 4,256,652, 4,271,085, 4,329,299,4,431,666, 4,466,924, 4,560,781, 4,562,275, 4,575,550, 4,578,491,4,584,316, 4,584,392, 4,599,352, 4,614,811, 4,658,047, 4,661,516,4,665,210, 4,670,458, 4,675,336, 4,680,308, 4,687,780, 4,720,504,4,739,087, 4,758,588, 4,760,155, 4,760,156, 4,760,157, 4,845,124,4,861,905, 4,968,826, 5,011,959, 5,041,578, 3,194,645, 5,244,919,5,288,887, 5,393,909, 5,434,256, 5,519,155, 5,665,771 and 6,008,395,which also describe the synthesis of these agents from platinum (II) orplatinum (IV) halides or from substances which can be synthesisedtherefrom by well-known reactions. The disclosure of the abovereferenced United States patents is incorporated herein by reference.

[0045] Typically, in the methods of the forth, fifth and seventhembodiments, the step of monitoring the subject includes the step ofmonitoring the uptake of the platinum radiolabelled chemotherapeuticagent in the subject, typically in a localised area of the subject.Still more typically, the step of monitoring is achieved by imagingmeans. Additionally or alternatively the step of monitoring the subjectmay further comprise the step of monitoring the clearance of theradiolabelled chemotherapeutic agent from the subject.

[0046] Still more typically in the methods of the fourth, fifth andseventh embodiments, the step of monitoring the subject comprisesmonitoring relative uptake of the radiolabel in target and non-targetorgans to allow determination in the subject of the relative toxicity ofthe chemotherapeutic agent. Typically, the monitoring process seeks ahigh target to non-target ratio. For example, if a patient iscompromised in the excretory organs (i.e. kidneys are not functioningproperly) then the monitoring step allows a reassessment of the dosageto be provided to the subject. Hence, in cases where the target organshave relatively high uptake of the chemotherapeutic agent, the uptake innon-target organs should also be considered in the determination of thecorrect dosage. However, the critical factor is still whether thechemotherapeutic agent is absorbed in the target region.

[0047] In a typical application of a method of the fourth embodiment, apatient is diagnosed with some form of cancer by standard methods e.gCT, MRI, X-ray and biopsy, and is referred for chemotherapy byadministration of cisplatin. Although it is clearly important for thepatient to receive the appropriate dose, in current therapies theclinician will typically live estimates of an appropriate dose, but willbe unsure whether the patient will experience severe or mild sideeffects. The use of radiolabelled product prepared by the method of thepresent invention can provide the clinician with information on how thecisplatin distributes in that particular patient which can be used tomore effectively prescribe the appropriate dose. Additionally, ifmonitoring of uptake indicated that the product was going to take longerthan desired to clear from the kidneys, a clearing agent could beadministered. Further, knowledge of whether the product is taken up wellby the target (cancer) assists the clinician in the choice of theappropriate drug for treatment. That is, the clinician can determinewhether cisplatin is likely to be effective or whether some otherchemotherapeutic agent is indicated. Where the patient presents for asecond treatment the method of the fourth embodiment can be used toestablish if the product is still effective (that is, whether it isstill taken up at the target site and is clearing well from excretoryorgans.)

[0048] A method of assessment of the effectiveness of a treatment of adisease in accordance with the fourth embodiment of the inventiontypically comprises the steps of monitoring the selectivity of uptake ofthe platinum radiolabelled chemotherapeutic agent in a localised area ofthe subject which is the site of the disease, in order to determine theeffectiveness of the platinum chemotherapeutic agent against thedisease. The method of assessment can allow continuous monitoring atselected time intervals by imaging the platinum radiolabelledchemotherapeutic agent so as to determine the presence or absence ofcancer cells in tissue. Typically, in this method, over a certain periodof time, the localisation of the platinum chemotherapeutic agent withinthe diseased tissue can be monitored in a particular subject. Bymonitoring the platinum radiolabelled chemotherapeutic agent in thesubject it may be determined whether there is any resistance to theparticular chemotherapeutic agent or whether the chemotherapeutic agentis effective against the disease.

[0049] Typically, the method of assessment will further comprise a stepof determining the extent of any cancer cells in the subject bymonitoring the increase or reduction of cancer cells in the subject overtime.

[0050] Thus the method of assessment permits assessing drug resistancein a subject after administration of the platinum radiolabelledchemotherapeutic agent. If the subject shows over a period of time thatthe number of cancer cells is not being reduced, or that the particulartissue does not retain the chemotherapeutic agent, then an alternativetherapy may be instigated, such as administration of otherchemotherapeutic agents and/or external radiation.

[0051] More typically, the method of assessment further comprises thestep of administering a composition of a mostly unradiolabelled or“cold” platinum chemotherapeutic agent with an amount of theradiolabelled chemotherapeutic agent to a subject. The composition ofthe two components is blended in a known ratio. Typically, theproportion of the radiolabelled chemotherapeutic agent to theunradiolabelled therapeutic agent is 5 to 8 percent (5 to 8 mg ofradiolabelled chemotherapeutic agent with 100 mg of the “cold”chemotherapeutic agent). The administration of this composition allowsassessment of the selective uptake of a particular platinumchemotherapeutic agent by detection of the radiolabelled platinumchemotherapeutic agent in the said subject, particularly a localisedarea of said subject.

[0052] A method of diagnosis of the fifth embodiment and a method ofprognosis of the seventh embodiment will typically comprise the step ofmonitoring the selective uptake of the radiolabelled chemotherapeuticagent throughout the subject in order to determine the presence orabsence of a disease or extent of disease. The method of diagnosis ormethod prognosis will typically comprise administration of a platinumradiolabelled chemotherapeutic agent which has been radiolabelled with aradionuclide having imaging culpability. More typically, theradiolabelled chemotherapeutic agent will allow the detection andtracking of the platinum chemotherapeutic agent throughout the subjectby use of imaging means. The imaging step will determine the presenceof, or extent of, disease throughout the subject by identifying cancercells in the subject after uptake of the chemotherapeutic agent. This isshown by localisation of the radiolabelled chemotherapeutic agent in aparticular subject.

[0053] A method of therapy in accordance with the sixth embodiment ofthe invention typically comprises the administration of a composition ofa radiolabelled chemotherapeutic agent which has a therapeutic level ofradioactivity and emission. Typically, in this method the radiolabelledplatinum chemotherapeutic agent emits an auger or beta emission whichacts to split the DNA of cancer cells. The auger or beta emission canthus act to enhance the chemotherapeutic properties of the radiolabelledplatinum chemotherapeutic agent.

[0054] It is to be understood that the term “effective amount” for eachof the method of diagnosis, prognosis, assessment or therapy shall varyand depend upon the particular requirements of each method. It isexpected that these “effective amounts” shall vary depending on a numberof factors including the selected cancer, tissue and particularrequirements of the subject. Given the teaching herein, cliniciansapplying the methods of the present invention will have no difficulty indetermining effective amounts of radiolabelled platinum chemotherapeuticagents.

[0055] A further application of compounds of the third embodiment is inrisk assessment, especially of newly developed candidatechemotherapeutic agents containing platinum. In such an application, amethod of the first embodiment provides the chemotherapeutic agentcontaining a radiolabel, whose distribution and uptake in an animal canbe assessed much more readily than can the distribution and uptake ofthe corresponding unradiolabelled substance. The use of theradiolabelled substance allows dynamic studies to be performed whichreadily provide more accurate information for determiningpharmacokinetics of the substance.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0056] In Scheme 1, there is shown in schematic form a prior art processfor producing radiolabelled cisplatin from Pt metal. This processcomprises irradiating enriched ¹⁹⁴Pt metal in a high flux nuclearreactor (designated ‘HIFAR’ in the Schemes). The irradiated ¹⁹⁴Pt isthen treated with aqua regia (HCl/HNO₃) to form H₂PtCl₆, H₂PtCl₆ is thentreated with NaCl to form Na₂PtCl₆ which in turn is reacted withhydrazine to form Na₂PtCl₄, Na₂PtCl₄ is reacted with KI to form K₂PtI₄,which is converted to Pt(NH₃)2I₂ reaction with NH₄OH. Pt(NH₃)₂I₂ isreacted width AgNO₃ to form Pt(NH₃)₂(H₂O)₂(NO₃)₂ which is then reactedwith HCl to form cisplatin. The synthesis time from conclusion ofirradiation of ¹⁹⁴Pt to formation of cisplatin is typicallyapproximately 6.5 hours and in 21 replicate experiments the yield rangedfrom 0 to 30% with an average yield of 8.4%. Six of these replicatesgave zero yield.

[0057] In Scheme 2, there is shown in schematic form a process accordingto the present invention for producing cisplatin. Enriched Pt-194 metalis treated with aqua regia (HCl/HNO₃) to form H₂PtCl₆, H₂PtCl₆ issubjected to thermal decomposition via a furnace to form Pt(II)Cl₂.Pt(II)Cl₂ is then subjected to irradiation in a high flux nuclearreactor and reacted with KI to form K₂Ptl₄, which is converted tocisplatin by the same steps as described above. The synthesis time fromconclusion of irradiation of PtCl₂ to formation of cisplatin istypically about 1.5 hours and in ten replicates the yield ranged from56.7 to 61.6%, averaging 60.1%.

[0058] Scheme 3 shows in schematic form a process according to thepresent invention for producing carboplatin. In this process. Pt(II)Cl₂radiolabelled with ^(195m)Pt is prepared in the same way as describedabove with reference to Scheme 2 and converted to K₂PtI₄ as describedabove with reference to Scheme 2. Conversion of the radiolabelled K₂PtI₄to radiolabelled carboplatin involves the steps of treating the K₂PtI₄with NH₄OH to produce Pt(NH₃)₂I₂ and converting this to carboplatin byreaction with silver cyclobutanedicarboxylate (AgCBCDA). The synthesistime from conclusion of irradiation of PtCl₂ to formation of carboplatinis typically about 1.75 hours.

EXAMPLES OF THE INVENTION

[0059] The following examples serve to illustrate the invention andshould not be construed as limiting the generality of the abovedescription.

Example 1 Preparation of PtCl₂

[0060] Conversion of Pt(0) to Pt(IV)

[0061] Enriched Pt-194 metal (>95%; 359 mg) was digested in ˜2 mL aquaregia at 120° C. with a N₂ stream above the solution. The solution washeated until it turned dark orange (approximately 20 minutes). Thesolution was transferred to another glass tube and evaporated to drynessunder Na on the borplate. A further 2 ml of arma regia was added to theoriginal tube containing the Pt metal and this process was repeateduntil all the metal was digested. The solutions were combined andevaporated to dryness under N₂. The residue was further digested withapproximately 1 mL concentrated HCl and evaporated to dryness under N₂to yield H₂PtCl₆.

[0062] Thermal Decomposition

[0063] The H₂PtCl₆ (0.40 gm) was transferred to a ceramic boat anddecomposed to PtCl₂ by heating in a furnace over a range of temperaturesfrom 20-300° C. over a 2 hr period in the presence of air. The resultantPtCl₂ powder was characterised by x-ray crystallography. Recovery ofPtCl₂ product was >90% of theoretical yield, based on Pt metal.

Example 2 Synthesis of [^(195m)Pt]Cisplatin

[0064] Approximately 60 mg of PtCl₂ is irradiated for at least 8 days ina high flux nuclear reactor. Once irradiation is complete the[^(195m)Pt]PtCl₂ (54.98 mg) is transferred to a kimble tube and thensuspended in 100 μl of a solution of 0.1 M HCl. To this mixture is thenadded 300 μl of 4 M KI followed by 100 μl of concentrated ammonia. Ayellow precipitate forms |(NH₃)2PtI₂] and tfie solution becomes brown.The mixture is gently warmed in a 50° C. water bath for approximately 5minutes. The mixture is then centrifuged for 3 minutes at 6000 rpm andthe supernatant is transferred to another test tube. The precipitate iswashed with 800 μl of 0.01 M KI and centrifuged for 3 minutes at 6000rpm. To the first supernatant another 28 μl of concentrated ammonia isadded to ensure all the (NH₃)₂PtI₂ has precipitated, and the solution iswarmed for 5 minutes in a 50° C. bath. The resulting mixture iscentrifuged for 3 minutes at 6000 rpm, the supernatant is removed andthe precipitates combined using 400 μl 0.1 M KI. To the resultantmixture of (NH₃)₂PtI₂ in 0.1 M KI is then added 0.4 M AgNO₃ (1.1 mL)slowly to form (NH₃)₂Pt(H₂O)₂(NO₃)₂. This tine a pale l(i fellowprecipitate forms (AgI) and the solution becomes clear. The mixture iscentrifuged for 3 minutes at 6000 rpm and the supernatant is removed.The remaining AgI is washed with 8001 μl of 0.01 M NaNO₃ and thesupernatants are combined. To remove any remaining Ag⁺, 140 μL of 1.0 MHCl is added to the supernatant and the white precipitate is removedafter centrifugation (3 minutes/6000 rpm). A final test for the presenceof any Ag⁺ is done by adding a further 40 μL of 1.0 M HCl. If noprecipitate forms 400 μL of concentrated HCl is added and the solutionis heated for 5 minutes at 50° C. The solution becomes a clear yellowand a yellow precipitate forms, which is [^(195m)Pt]cisplatin. Theyellow precipitate is collected by filtration and washed with chilledethanol and acetone (2 mL). Yield 43.3 mg (70%). The precipitate is thendissolved in 40 mL of saline. The solution is monitored by UV/V isspectroscopy and the purity of the product is determined by calculatingthe ratio of absorbance at 301 and 365 nm to be 5.4±0.2. GammaSpectrometry showed radionuclidic in purity to be >95% and finalspecific activity to be 4.0 MBq/mg.

Example 3 Synthesis of [^(195m)Pt]Carboplatin

[0065] Starting with 62.14 mg of [^(195m)Pt]Ptcl₂ prepared as describedabove, the synthesis of [^(195m)Pt]carboplatin is similar to thatdescribed above except for the following changes. The kimble tubecontaining the mixture of (NH₃)₂PtI₂ in 0.1 M KI is covered in aluminumfoil to prevent light from entering, and then 45 mg of silvercyclobutanedicarboxylate is added followed by 800 μL of water. Themixture is then sonicated at 50° C. for 20 minutes in the dark andcentrifuged for 3 minutes at 6000 rpm. The supernatant is transferred toa 50 mL beaker and approximately 30 mL of chilled acetone is added. Themixture is left in the fridge at about 5° C. overnight or 30 minutes at−4° C. The clear crystals of [^(195m)Pt]carboplatin which form arefiltered off and dried under vacuum. Yield 29.45 mg (33.95%). Theproduct is then dissolved in saline and the chemical and radionuclidicpurity is checked by HPLC and gamma spectrometry. The final product hasa chemical and radionuclidic purity >95%. Specific activity of the finalproduct is >3 MBq/mg.

Example 4 Pilot Clinical Study

[0066] This Example illustrates the usefulness of radiolabelled platinumbased chemotherapeutic agents in predicting the likely response of apatient to treatment by non-radiolabelled platinum basedchemotherapeutic agents and hence the role of the radiolabelled agentsas prognostic indicators for the patient outcome.

[0067] As part of a pilot study to evaluate the use of^(195m)Pt-Cisplatin and ^(195m)Pt Carboplatin for prognosis of cancer,two patients were injected with ^(195m)Pt-Cisplatin prepared asdescribed in Example 2.

[0068] Patient No.1 had oesophageal cancer, with one large lesion in themediastinal region and large metastases in the liver. F-18-DG imagingconfirmed the presence of both lesions. The patient was injected with^(195m)Pt-Cisplatin (100 MBq; specific activity 4.2 MBq/rug cisplatin)and imaged over a 5 day period. This patient showed negligible uptake ofthe radiolabelled cisplatin in both lesions. The patient was placed on anormal cisplatin chemotherapy in combination with radiation. After 2months no evidence of response to treatment was noted.

[0069] Patient No.2 had oesophageal cancer. CT confirmed a large lesionin the mediastinal region. The patient was injected with^(195m)Pt-Cisplatin (50 MBq: specific activity 3.6 MBq/mg cisplatin) andImaged over a 3 day period. The images showed significant uptake of the^(195m)Pt-Cisplatin in the mediastinal region. The patient has undergonecisplatin chemotherapy and is being monitored for response to treatment.

[0070] The two patient studies show significant difference in uptake of^(195m)-Pt-Cisplatin illustrating the potential of the agent to assistin selecting patients that ate most likely to respond to cisplatinchemotherapy.

[0071] The images obtained after administering radiolabelled platinumbased chemotherapeutic agents can also be used to monitor uptake in andclearance from non-target organs (for example liver and kidneys).Information obtained regarding clearance rates can be used to assist inestimation of the appropriate dose of the cisplatin chemotherapeutic forindividuals. The ability to predict the type and extent of side effectshas a role in minimising irreversible damage caused by anover-estimation of chemotherapeutic agent.

[0072] The advantages of the invention reside in a reduced synthesistime of approximately 1.5 h for cisplatin and 1.75 h for carboplatin, aswell as higher and more reliable yields (greater than 50%) and reducedrisk of a failed synthesis (estimated at less than approximately 1%.)

[0073] Modifications and variations such as would be apparent to askilled addressee are deemed to be within the scope of the presentinvention. It is to be understood that the present invention is notlimited to the particular embodiment(s) described above.

1. A method of synthesis of a radiolabelled platinum chemotherapeuticagent comprising the steps of: a) converting a metal halide to aradiolabelled platinum halide wherein the radiolabel is a radioisotopeof Pt; and b) synthesising the radiolabelled platinum chemotherapeuticagent from the radiolabelled platinum halide.
 2. A method according toclaim 1 wherein said radiolabelled platinum chemotherapeutic agent isselected from compounds of the general formulae (I) and (II):

where each A is independently selected from halo, hydroxy, alkoxy andcarboxylate or in which two A ligands together form a bi-dentate ligand;each B, which may be the same or different, is selected from halo,hydroxy, carboxylate, carbarnate and carbonate ester; Z and X areindependently NH₃, cyclic amine, alkylamino, arylamino, cycloalkylamino,and aralkylamino, or Z and X together are H₂N-Q-NH₂ wherein Q is adivalent moiety selected from alkylene, cycloalkyl, aryl and aralkyl. 3.A method according to claim 2 wherein said radiolabelled platinumchemotherapeutic agent is of formula I and X, Z and A are as defined inclaim
 2. 4. A method according to claim 2 wherein each A is the same andis chloro, or wherein two A ligands, taken together, formcyclobutane-1,1-dicarboxylate or sulfate.
 5. A method according to claim1 wherein said platinum chemotherapeutic agent is cisplatin orcarboplatin.
 6. A method according to claim 1 wherein said radiolabelledplatinum halide is a radiolabelled Pt(II) halide.
 7. A method accordingto claim 6 wherein said radiolabelled Pt(II) halide is radiolabelledPtCl₂.
 8. A method of synthesis of cisplatin or carboplatin comprisingthe steps of: a) converting a metal chloride to radiolabelled PtCl₂wherein the radiolabel is a radioisotope of Pt; and b) synthesisingcisplatin or carboplatin from the radiolabelled PtCl₂.
 9. Aradiolabelled platinum chemotherapeutic agent produced bay the method ofsynthesis of any one of claims 1-8.
 10. Use of a radiolabelled platinumchemotherapeutic agent according to claim 9 for the preparation of amedicament for diagnosis, prognosis, therapy or assessment of theeffectiveness of treatment of a disease.
 11. Use according to claim 10wherein said disease is cancer.
 12. A method of assessing theeffectiveness of treatment of a disease wherein said treatment comprisesadministration of a platinum chemotherapeutic agent to a subject whichmethod comprises the steps of administering to said subject a platinumchemotherapeutic agent according to claim 9, in an amount sufficient topermit uptake or clearance of said radiolabel to be monitored in saidsubject and monitoring said subject.
 13. A method of diagnosis of adisease in n subject comprising the steps of administering an effectiveamount of a platinum chemotherapeutic agent according to claim 9 to saidsubject and monitoring said subject.
 14. A method of therapy of adisease in a subject comprising the steps of administering an effectiveamount of a platinum chemotherapeutic agent according to claim 9 to saidsubject.
 15. A method of prognosis of a disease in a subject comprisingthe steps of administering an effective amount of a platinumchemotherapeutic agent according to claim 9 to said subject andmonitoring said subject.